Tumorigenesis involves sequential genetic lesions in pathways that regulate fundamental biological processes such as cell proliferation and cell survival (Hahn & Weinberg (2002) Nat. Rev. Cancer 2:331-41; Vogelstein & Kinzler (2004) Nat. Med. 10:789-99). It has been suggested that both the p16Ink4a-CycD/Cdk4-pRb and Arf-MDM2/MDMX-p53 pathways must be inactivated during tumorigenesis (Vogelstein & Kinzler (2004) supra).
The primary role of the Rb pathway is to regulate cell proliferation (Sherr & McCormick (2002) Cancer Cell 2:103-112; Chau & Wang (2003) Nat. Rev. Cancer 3:130-8), and that of the p53 pathway is to regulate responses to cellular insults such as DNA damage or oncogenic stress (Vogelstein, et al. (2000) Nature 408:307-10; Oren (2003) Cell Death Differ. 10 431-42; Prives & Hall (1999) J. Pathol. 187:112-26). The Rb and p53 pathways may be inactivated by mutations in the RB1 and p53 tumor suppressor genes themselves or through genetic alterations of genes encoding modulators and/or effectors in these pathways.
For example, some cancers have MDM2 gene amplifications that functionally suppress the p53 pathway by reducing the steady-state levels of the p53 protein (Honda, et al. (1997) FEBS Lett. 420:25-7; Kubbutat, et al. (1997) Nature 387:299-303; Momand, et al. (1998) Nucl. Acids Res. 26:3453-9). When MDM2-mediated destabilization of p53 is blocked by the inhibitor nutlin-3 in tumors with MDM2 gene amplifications, the p53 pathway is restored, and tumor cells undergo p53-mediated cell cycle arrest, cell death, or both (Yang, et al. (2005) Cancer Cell 7:547-59; Vassilev, et al. (2004) Science 303:844-8). Therefore, identification of genetic perturbations in the Rb and p53 pathways can provide specific targets for chemotherapy.
Genetic evidence has shown that when a p53 mutation is the tumor-initiating event, subsequent genetic lesions such as loss of the p16INK4A gene disrupt the Rb pathway (Guran, et al. (1999) Cancer Genet. Cytogenet. 113:145-51; Rogan, et al. (1995) Mol. Cell. Biol. 15:4745-53). However, retinoblastomas that arise from cells that have lost RB1 have not been found to contain subsequent genetic lesions in the p53 gene (Kato, et al. (1996) Cancer Lett. 106:75-82) or pathway (Nork, et al. (1997) Arch Opthalmol. 115:213-219). Recent genetic studies in Rb; p107-deficient mouse retinae have extended these findings and led to the proposal that retinoblastoma is a unique tumor that bypasses the p53 pathway because the cell of origin is intrinsically death resistant (Dyer & Bremner (2005) Nat. Rev. Cancer 5:91-101).
It has been suggested that inactivation of the Rb pathway is sufficient for retinoblastoma formation because the Arf-MDM2/MDMX-p53 oncogenic stress response pathway is never activated (Dyer & Bremner (2005) supra). This has important implications for cancer genetics and treatment. It suggests that depending on the cell-of-origin, cancer can proceed down a “fast track” of tumorigenesis, because the cells are intrinsically programmed to bypass certain tumor suppressor pathways (Dyer & Bremner (2005) supra). Thus, therapeutic targets may differ depending on the initiating genetic lesion and the pathways bypassed.